Urocortins Brain CRF2 Receptors and Energy Balance

描述(由申请人提供)：2型尿皮质素是促肾上腺皮质激素释放因子2型(CRF2)系统的新型配体，在喂食由可口的高脂肪和精制碳水化合物组成的能量密集型“自助”饮食的大鼠中，保留了它们的中枢厌食特性。这一发现是有希望的，因为对厌食剂的不敏感是肥胖治疗的障碍。目前的应用假设脑促肾上腺皮质激素释放因子2型(CRF2)系统是抑制体重增加的内源性反向调节系统的下游组件。选择性CRF2配体颅内输注的急性和慢性影响将在选择性培育的大鼠品系中进行研究，这些品系对饮食诱导的肥胖具有不同的易感性。神经药理学研究将在不同的饮食条件下进行，其中一些会导致肥胖，以确定在肥胖风险、高脂饮食史或明显肥胖的情况下，2型尿皮质激素的厌食特性是否保持不变。间接量热法和配对喂养研究将检查CRF2配体改变体重的代谢成分与基因和饮食之间的关系，并具有脑部位特异性。连续的实质内CRF2配体治疗对肥胖和血糖调节的长期效果将在无治疗状态下进行比较。CRF受体在中枢瘦素和胰岛素输注的能量平衡相关效应中的作用将使用亚型特异性拮抗剂进行测试。微结构分析的创新形式和操作反应的渐进时间表将被用来识别2型尿皮质激素控制食物摄入的行为结构。将考虑其他解释，如不适。拟议的研究将确定一般和大脑CRF受体相关的摄食模式和代谢差异，这些差异与肥胖和节食史有关。相关性：有效的肥胖治疗方法很少，部分原因是肥胖者对有助于调节体重的生物信号产生抵抗力。大脑机制仍然可以促进肥胖者和那些能够获得美味食物的人的体重减轻，这对公众健康具有重大意义。本申请使用新的药理学工具来研究最近发现的神经肽系统通过食欲和代谢的变化在控制体重中的作用，这一发现可能确定治疗肥胖症及其相关医疗并发症的治疗目标。

DESCRIPTION (provided by applicant): Type 2 urocortins, novel ligands for corticotropin-releasing factor type 2 (CRF2) systems, retain their central anorectic properties in rats fed an energy dense "cafeteria" diet composed of palatable high fat and refined carbohydrate foods. This finding is promising because developing insensitivity to anorectics is an obstacle to obesity treatment. The present application hypothesizes that brain corticotropin- releasing factor type 2 (CRF2) systems are downstream components of the endogenous counter-regulatory system that curbs body weight gain. Acute and chronic effects of intracranial infusion of selective CRF2 ligands will be studied in rat lines selectively bred for differential vulnerability to diet-induced obesity. Neuropharmacologic studies will be performed under different dietary conditions, some of which promote obesity, to determine whether the anorectic properties of type 2 urocortins are retained despite obesity risk, high-fat diet history or manifest obesity. Indirect calorimetry and pair-feeding studies will examine metabolic components of the body weight-altering effects of CRF2 ligands in relation to genotype and diet with brain- site specificity. Long-term effects of continuous, intra-parenchymal CRF2 ligand treatment on adiposity and glucose regulation will be compared in treatment-free states. The role of CRF receptors in the energy balance-related effects of central leptin and insulin infusion will be tested using subtype-specific antagonists. Innovative forms of microstructure analysis and progressive schedules of operant responding will be used to identify the behavioral construct through which type 2 urocortins control food intake. Alternative explanations, such as malaise, will be considered. The proposed studies would identify general and brain CRF receptor- related differences in feeding patterns and metabolism that are associated with obesity and diet history. Relevance: Effective obesity treatments are few in part because obese individuals become resistant to biological signals that otherwise help regulate body weight. Brain mechanisms that can still promote weight loss in obese individuals and those with access to palatable foods are of great public health interest. The present application uses new pharmacological tools to study the role of a recently identified neuropeptide system in the control of body weight, via changes in appetite and metabolism, findings which may identify a therapeutic target for the treatment of obesity and its related medical complications.